P816: TRANSIENT MONOSOMY 7 IN SAMD9/9L SYNDROMES: IS IT SAFE TO WATCH AND WAIT?
Authors: M. Erlacher, F. Andresen, A. Yoshimi, M. Sukova, J. Stary, B. de Moerloose, M. Dworzak, S. Polychronopoulou, G. Göhring, C. Kratz, J. van der Werff ten Bosch, M. Seidel, B. Strahm, M. Wlodarski, C. Niemeyer
Journal: HemaSphere (2022)

Background: Monosomy 7 is a non-random but poorly understood somatic event in myelodysplastic syndrome (MDS). Most enigmatic is the fact that monosomy 7 can disappear spontaneously. Such transient monosomy 7 was recently associated with germline mutations in sterile alpha-motif domain-containing protein 9 (SAMD9) and its paralog SAMD9-like (SAMD9L), both located on chromosome 7q. Mechanistically, gain-of-function (GOF) SAMD9/9L mutations inhibit proliferation and reduce survival in different cell types thus leading to bone marrow failure, immunodeficiency and non-hematological phenotypes. Hematopoietic cells are under a high selection pressure to inactivate this toxic gene and achieve this by multiple mechanisms: uniparental disomy, monosomy 7, del(7q) or somatic loss-of-function (LOF) mutations of the mutated allele. Multiple “rescued” clones exist in parallel within the bone marrow of patients, and dominance of an UPD or somatically mutated clone can displace the monosomy 7 clone and result in hematological remission. Aims: We recently identified SAMD9/9L mutations in 8% of children with MDS, and a strong association with monosomy 7 (EWOG-MDS; Sahoo et al, Nat Med, 2021). This retrospective analysis revealed transient monosomy 7 and spontaneous hematological remission in some infants. To prospectively study the propensity of patients to lose their monosomy 7 clone, EWOG-MDS elected to delay immediate hematopoietic stem cell transplantation (HSCT) in children <5 years of age diagnosed of refractory cytopenia (RCC) with germline SAMD9/9L mutation and monosomy 7. Methods: Patients with SAMD9 or SAMD9L mutation and monosomy 7, younger than 5 years of age, were closely monitored with bone marrow morphology, SAMD9/9L mutational analysis and cytogenetic studies every 3-4 month. HSCT was recommended in case of severe infections, persistent severe neutropenia, progression with additional cytogenetic aberrations or increase in blasts (MDS-EB), or persistence of monosomy 7 beyond the age of 5 years. Results: Eight patients diagnosed at a median age of 11 months (range 4-36 months) with SAMD9L (n=7) or SAMD9 (n=1) germline mutation were studied. Two (P5 and P8) were born small for gestational age, P5 presented with global developmental delay and cerebellar atrophy. With a median follow-up of 27 months, 6 of the 8 patients are alive. One patient succumbed to infection prior to HSCT (P4), another to transplantation-related toxicity (P8). HSCT was performed or is currently scheduled in 4 of the 8 patients; indications were severe neutropenia/infection (P5, P6), immunodeficiency (P7) or MDS-EB (P8). The monosomy 7 clone regressed in 3 patients (P1-P3) and was no longer detectable at 3 months (P1) or 1 year (P2) from diagnosis (P3 was lost to follow-up at 12 months). Somatic SAMD9L mutations were noted in P1 and P2, both of which experienced a complete hematological and cytogenetic recovery. In sum, we followed 8 patients with SAMD9/9L syndrome and monosomy 7. Transient monosomy 7 with hematological recovery was observed in 2 patients and accompanied by gain of somatic rescuing mutations. Summary/Conclusion: Transient monosomy 7 in young children with SAMD9/SAMD9L germline disorder and RCC with monosomy 7 is a rare event. Initiation of a watch and wait strategy instead of timely HSCT will require a stringent surveillance strategy including repetitive BM analyses for SAMD9/9L sequencing, cytogenetics and search for somatic oncogenic events.